Potassium is the most abundant intracellular cation in neurons. It is essential for maintaining the resting membrane potential and also for regulating cellular volume (Pasantes-Morales et al., J Neurosci Res 34, 219-224, 1993; Yu, Prog Neurobiol 70, 363-386, 2003). During injury, K+ efflux and intracellular K+ loss critically contribute to the apoptotic volume decrease (Bortner et al., J Biol Chem 272, 32436-32442, 1997; Maeno et al., Proc Natl Acad Sci USA 97, 9487-9492, 2000; Lang and Hoffmann, Compr Physiol 2, 2037-2061, 2012), a hallmark morphological feature of programmed cell death (Kerr et al., Br J Cancer 26, 239-257, 1972). In addition, reduced cytosolic K+ enables apoptosis by providing a permissive environment for activation of caspases and nucleases (Hughes et al., J Biol Chem 272, 30567-30576, 1997; Yu et al., Science 278, 114-117, 1997). Kv2.1, a voltage-dependent delayed-rectifier K+ channel normally involved in the regulation of high-frequency repetitive firing (Pongs, FEBS Lett 452, 31-35, 1999; Du et al., J Physiol 522, 19-31, 2000; Guan et al., J Physiol 591, 4807-4825, 2013), acts as the primary conduit for K+ efflux during apoptotic cell death in neocortical and hippocampal neurons (Pal et al., J Neurosci 23, 4798-4802, 2003; Shen et al., J Neurosci Res 87, 3153-3160, 2009). This process occurs via a syntaxin-dependent exocytotic incorporation of new Kv2.1-encoded channels into the plasma membrane of dying neurons, measurable as a large enhancement of voltage-dependent K+ currents (McLaughlin et al., J Neurosci 21, 3303-3311, 2001; Pal et al., J Neurosci 23, 2003; Pal et al., Cell Death Differ 13, 661-667, 2006). Inhibiting any of the upstream signaling events leading to the insertion of Kv2.1, or blocking Kv2.1 channel function itself, is neuroprotective (Yu et al., Science 278, 114-117, 1997; McLaughlin et al., J Neurosci 21, 3303-3311, 2001; Pal et al., J Neurosci 23, 4798-4802, 2003; Aras and Aizenman, Antioxid Redox Signal 15, 2249-63, 2011).